Coronary artery disease (CAD) is the major cause of death in Type 2 diabetic and metabolic syndrome patients (i.e. patients that fall within the ‘deadly quartet’ category of impaired glucose tolerance, insulin resistance, hypertriglyceridaemia and/or obesity).
The hypolipidaemic fibrates and antidiabetic thiazolidinediones separately display moderately effective triglyceride-lowering activities although they are neither potent nor efficacious enough to be a single therapy of choice for the dyslipidaemia often observed in Type 2 diabetic or metabolic syndrome patients. The thiazolidinediones also potently lower circulating glucose levels of Type 2 diabetic animal models and humans. However, the fibrate class of compounds are without beneficial effects on glycaemia. Studies on the molecular actions of these compounds indicate that thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased and decreased expression of specific enzymes and apolipoproteins respectively, both key-players in regulation of plasma triglyceride content. Fibrates, on the one hand, are PPARα activators, acting primarily in the liver. Thiazolidinediones, on the other hand, are high affinity ligands for PPARγ acting primarily on adipose tissue.
Adipose tissue plays a central role in lipid homeostasis and the maintenance of energy balance in vertebrates. Adipocytes store energy in the form of triglycerides during periods of nutritional affluence and release it in the form of free fatty acids at times of nutritional deprivation. The development of white adipose tissue is the result of a continuous differentiation process throughout life. Much evidence points to the central role of PPARγ activation in initiating and regulating this cell differentiation. Several highly specialised proteins are induced during adipocyte differentiation, most of them being involved in lipid storage and metabolism. The exact link from activation of PPARγ to changes in glucose metabolism, most notably a decrease in insulin resistance in muscle, has not yet been clarified. A possible link is via free fatty acids such that activation of PPARγ induces Lipoprotein Lipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoA Synthetase (ACS) in adipose tissue but not in muscle tissue. This, in turn, reduces the concentration of free fatty acids in plasma dramatically, and due to substrate competition at the cellular level, skeletal muscle and other tissues with high metabolic rates eventually switch from fatty acid oxidation to glucose oxidation with decreased insulin resistance as a consequence.
PPARα is involved in stimulating β-oxidation of fatty acids. In rodents, a PPARα-mediated change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis in rodents. The phenomenon of peroxisome proliferation is not seen in man. In addition to its role in peroxisome proliferation in rodents, PPARα is also involved in the control of HDL cholesterol levels in rodents and humans. This effect is, at least partially, based on a PPARα-mediated transcriptional regulation of the major HDL apolipoproteins, apo A-I and apo A-II. The hypotriglyceridemic action of fibrates and fatty acids also involves PPARα and can be summarised as follows: (I) an increased lipolysis and clearance of remnant particles, due to changes in lipoprotein lipase and apo C-III levels, (II) a stimulation of cellular fatty acid uptake and their subsequent conversion to acyl-CoA derivatives by the induction of fatty acid binding protein and acyl-CoA synthase, (III) an induction of fatty acid β-oxidation pathways, (IV) a reduction in fatty acid and triglyceride synthesis, and finally (V) a decrease in VLDL production. Hence, both enhanced catabolism of triglyceride-rich particles as well as reduced secretion of VLDL particles constitutes mechanisms that contribute to the hypolipidemic effect of fibrates.
PPARδ activation was initially reported not to be involved in modulation of glucose or triglyceride levels. (Berger et al., j. Biol. Chem., 1999, Vol 274, pp. 6718-6725). Later it has been shown that PPAR8 activation leads to increased levels of HDL cholesterol in dbldb mice (Leibowitz et al. FEBS letters 2000, 473, 333-336). Further, a PPARδ agonist when dosed to insulin-resistant middle-aged obese rhesus monkeys caused a dramitic dose-dependent rise in serum HDL cholesterol while lowering the levels of small dense LDL, fasting triglycerides and fasting insulin (Oliver et al. PNAS 2001, 98, 5306-5311).The same paper also showed that PPAR6 activation increased the reverse cholesterol transporter ATP-binding cassette A1 and induced apolipoprotein A1-specific cholesterol efflux. The involvement of PPARδ in fatty acid oxidation in muscles was further substantiated in PPARα knock-out mice. Muoio et al. (J. Biol. Chem. 2002, 277, 26089-26097) showed that the high levels of PPARδ in skeletal muscle can compensate for deficiency in PPARα. Taken together these observations suggest that PPARδ activation is useful in the treatment and prevention of cardiovascular diseases and conditions including atherosclerosis, hypertriglyceridemia, and mixed dyslipidaemia (WO 01/00603).
A number of compounds have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (U.S. Pat. No. 5,306,726, WO 91/19702, WO 95/03038, WO 96/04260, WO 94/13650, WO 94/01420, WO 97/36579, WO 97/25042, WO 95/17394, WO 99/08501, WO 99/19313, WO 99/16758 and WO 01/00603).
The following documents disclose various compounds with PPARγ activity: U.S. Pat. No. 5,063,240, EP 0597102, EP 0696585, WO 94/25448, JP 09291031, JP 08217766, WO 99/63983.
Glucose lowering as a single approach does not overcome the macrovascular complications associated with Type 2 diabetes and metabolic syndrome. Novel treatments of Type 2 diabetes and metabolic syndrome must therefore aim at lowering both the overt hypertriglyceridaemia associated with these syndromes as well as alleviation of hyperglycaemia.
This indicate that research for compounds displaying various degree of PPARα, PPARγ and PPARδ activation should lead to the discovery of efficacious triglyceride and/or cholesterol and/or glucose lowering drugs that have great potential in the treatment of diseases such as type 2 diabetes, dyslipidemia, syndrome X (including the metabolic syndrome i.e. impaired glucose tolerance, insulin resistance, hypertrigyceridaemia and/or obesity), cardiovascular diseases (including atherosclerosis) and hypercholesteremia.
Definitions
In the structural formulas given herein and throughout the present specification the following terms have the indicated meaning:
The terms “C1-n′-alkyl” wherein n′ can be from 2 through 6, as used herein, represent a linear or branched, saturated hydrocarbon chain having the indicated number of carbon atoms. Examples of such groups include, but are not limited to methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
The term “C3-n′-cycloalkyl” wherein n′ can be from 4 through 6, as used herein, alone or in combination, represent a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms. Examples of such groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The terms “C1-n′divalent saturated carbon chain” and “C1-n′-alkylene” wherein n′ can be from 2 through 6, as used herein, represent a divalent linear or branched, saturated hydrocarbon chain having the indicated number of carbon atoms. Examples of such groups include, but are not limited to methylene, ethylene, trimethylene, tetramethylene, propylene, ethylethylene, methylpropylene, ethylpropylene and the like.
The terms “C4-n′-Cycloalkylene” wherein n′ can be from 5 through 6, as used herein, represent a divalent saturated monocyclic hydrocarbon group having the indicated number of carbon atoms. Examples of such groups include, but are not limited to cyclopentylene, cyclohexylene and the like.
The term “C2-n′-alkenyl” wherein n′ can be from 3 through 6, as used herein, represent an olefinically unsaturated branched or straight hydrocarbon group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl and the like.
The term “C2-n′-alkenylene” wherein n′ can be from 3 through 6, as used herein, represent an divalent olefinically unsaturated branched or straight hydrocarbon group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to ethenylene (—CH═CH—), the propenylene isomers (e.g., —CH2CH═CH— and —C(CH3)═CH—), the butenylene isomers (e.g., —CH2CH═C(CH3)—and —CH2CH2CH═CH—) and the like.
The terms “C4-n′-alkenynyl” as used herein, represent an unsaturated branched or straight hydrocarbon group having from 4 to the specified number of carbon atoms and both at least one double bond and at least one triple bond. Examples of such groups include, but are not limited to, 1-penten-4-yne, 3-penten-1-yne, 1,3-hexadiene-5-yne and the like, especially preferred is 1-pentene-4-yne.
The term “C4-n′-cycloalkenylene” wherein n′ can be from 5 through 6, as used herein, represent an divalent unsaturated monocyclic hydrocarbon group having from 4 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to cyclohexenylene and the like.
The term “C3-n′-alkynyl” wherein n′ can be from 4 through 6, as used herein, represent an unsaturated branched or straight hydrocarbon group having from 2 to the specified number of carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.
The term “C2-n′-alkynylene” wherein n′ can be from 3 through 6, as used herein, represent an divalent unsaturated branched or straight hydrocarbon group having from 2 to the specified number of carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, propynylene (—CH2C≡C—), the butynylene isomers (e.g., —CH2CH2C≡C—, —CH2C≡C—CH2—), and the like.
The term “C4-n′-alkenynylene” wherein n′ can be from 5 through 9 as used herein, represent an divalent unsaturated branched or straight hydrocarbon group having from 4 to the specified number of carbon atoms and both at least one double bond and at least one triple bond. Examples of such groups include, but are not limited to, 1-penten-4-ynylene, 3-penten-1-ynylene, 1,3-hexadiene-5-ynylene and the like.
The term “C3-n′-divalent unsaturated carbon chain” wherein n′ can be from 4 through 9, as used herein, represent an divalent unsaturated branched or straight hydrocarbon group having from 3 to the specified number of carbon atoms and at least one double bound (alkenylen) or at least one triple bound (alkynylene) or a combination hereof (alkenynylene). Examples of such groups include, but are not limited to ethenylene (—CH═CH—), the propenylene isomers (e.g., —CH2CH═CH— and —C(CH3)═CH—), the butenylene isomers (e.g., —CH2CH═C(CH3)— and CH2CH2CH═CH—), propynylene (—CH2C≡C—), the butynylene isomers (e.g., —CH2CH2C≡C—, —CH2C≡C—CH2—), 1-penten-4-ynylene, 3-penten-1-ynylene, 1,3-hexadiene-5-ynylene and the like.
The term “C1-n′-alkoxy” wherein n′ can be from 2 through 6, as used herein, alone or in combination, refers to a straight or branched configuration linked through an ether oxygen having its free valence bond from the ether oxygen. Examples of such linear alkoxy groups include, but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like. Examples of such branched alkoxy include, but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy and the like.
The term “C3-n′-Cycloalkoxy” wherein n′ can be from 4 through 6, as used herein, alone or in combination, represent a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms linked through an ether oxygen having its free valence bond from the ether oxygen. Examples of such cycloalkoxy groups include, but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
The term “C1-n′-alkylthio” wherein n′ can be from 2 through 6, as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a C1-6-alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 6 carbon atoms. Examples of such groups include, but are not limited to methylthio, ethylthio, propylthio, butylthio, pentylthio and the like.
The term “C3-n′-cycloalkylthio” wherein n′ can be from 4 through 6, as used herein, alone or in combination, represent a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms linked through a divalent sulfur atom having its free valence bond from the sulfur atom. Examples of such cycloalkoxy groups include, but are not limited to cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
The term “aryl” as used herein refers to an aromatic monocyclic or an aromatic fused bi- or tricyclic hydrocarbon group. Examples of such groups include, but are not limited to phenyl, naphthyl, anthracenyl, phenanthrenyl, azulenyl, fluorenyl and the like.
The term “arylene” as used herein refers to divalent aromatic monocyclic or a divalent aromatic fused bi- or tricyclic hydrocarbon group (derived from aryl). Examples of such groups include, but are not limited to phenylene, naphthylene, fluorenylene and the like.
The term “heteroaryl” as used herein, alone or in combination, refers to a divalent substituent comprising a 5-7 membered monocyclic aromatic system or a 8-10 membered bicyclic fused aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur or a 10-16 membered tricyclic fused aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur e.g. furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinnyl, indolyl, benzimidazolyl, benzofuranyl, pteridinyl, purinyl, carbazolyl, β-carbolinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl and the like The term “heteroarylene” as used herein, alone or in combination, refers to a divalent substituent (derived from heteroaryl) comprising a 5-7 membered monocyclic aromatic system or a 8-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur or a 10-16 membered tricyclic fused aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur e.g. furylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyrazinylene, pyrimidinylene, pyridazinylene, isothiazolylene, isoxazolylene, oxazolylene, oxadiazolylene, thiadiazolylene, quinolylene, isoquinolylene, quinazolinylene, quinoxalinnylene, indolylene, benzimidazolylene, benzofuranylene, pteridinylene, purinylene carbazolylene, β-carbolinylene, acridinylene, phenanthrolinylene, phenazinylene, phenoxazinylene, phenothiazinylene and the like.
The term “a divalent polycyclic ringsystem” as used herein refers to a divalent group formed from a polycyclic ringsystem containing indenpending of each other 2 trough 4 aryl or heteroaryl ring systems joined by single bonds. Example of such bi-, ter- and quaterarylylene having 2 through 4 identical aryl ring systems include, but are not limited to biphenylylene, binaphthylylene, terphenylylene, temaphthylylene, quaterphenylylene, quatemaphthylylene and the like. Example of such bi-, ter- and quaterheteroarylylene having 2 through 4 identical heteroaryl ring systems include, but are not limited to bipyridylylene, biindolylylene, terpyridylylene, terindolylylene, quaterpyridylylene, quaterindolylylene and the like. Example of such polycyclic ringsystems having non identical ring systems include, but are not limited to diphenylpyridine and the like.
The term “aralkoxy” as used herein refers to a C1-6-alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like.
The term “aralkyl” as used herein refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydride; such as benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl and the like.
The term “halogen” means fluorine, chlorine, bromine or iodine.
The term “treatment” as used herein includes treatment, prevention and management of conditions mediated by Peroxisome Proliferator-Activated Receptors (PPAR).
Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
The term “optionally substituted” as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.